Polymorphism in the IL18 Gene and Epithelial Ovarian Cancer in Non-Hispanic White Women
Polymorphism in the IL18 Gene and Epithelial Ovarian Cancer in Non-Hispanic White Women
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DOI：
10.1158/1055-9965.epi-08-0548
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发表时间：
2008-12-01
影响因子：
3.8
通讯作者：
Schildkraut, Joellen M.
中科院分区：
文献类型：
--
作者：
Palmieri, Rachel T.;Wilson, Melanie A.;Schildkraut, Joellen M.
2007年，美国诊断出超过22，000例卵巢癌病例，但其中只有一小部分可归因于BRCA 1等高度外显基因的突变。为了确定低突变率遗传变异是否会导致卵巢癌风险，我们使用定制的Illumina阵列对北卡罗来纳州卵巢癌研究（NCO）中848例上皮性卵巢癌病例和798例对照的几个候选基因通路中的1，536个单核苷酸多态性（SNP）进行了基因分型。炎症基因白细胞介素-18（IL-18）在逐基因分析中显示出与上皮性卵巢癌相关的最强证据（P = 0.002），假阳性发现的可能性< 25%（q值= 0.240）。使用多变量模型搜索算法对11个IL 18标记SNP进行搜索，我们发现rs 1834481最好地模拟了这种关联。此外，该SNP独特地标记了显著相关的IL 18单倍型，并且每个rs 1834481等位基因的上皮性卵巢癌风险增加（优势比，1.24; 95%置信区间，1.06-1.45）。在复制阶段，来自卵巢癌协会联盟（OCAC）的12项独立研究在另外5，877例病例和7，791例对照中对rs 1834481进行了基因分型。当12项OCAC研究的数据合并时，每个rs 1834481等位基因的固定效应估计值为零（比值比，0.99; 95%置信区间，0.94-1.05）。在添加了最初的北卡罗来纳州卵巢癌研究数据后，效应估计值保持不变。这一分析显示了联合体的重要性，如OCAC，在确认或反驳小样本研究中假定结果的有效性。（癌症流行病学生物标志物Prev 20081-17（12）：3567-72）
Over 22,000 cases of ovarian cancer were diagnosed in 2007 in the United States, but only a fraction of them can be attributed to mutations in highly penetrant genes such as BRCA1. To determine whether low-penetrance genetic variants contribute to ovarian cancer risk, we genotyped 1,536 single nucleotide polymorphisms (SNP) in several candidate gene pathways in 848 epithelial ovarian cancer cases and 798 controls in the North Carolina Ovarian Cancer Study (NCO) using a customized Illumina array. The inflammation gene interleukin-18 (IL18) showed the strongest evidence for association with epithelial ovarian cancer in a gene-by-gene analysis (P = 0.002) with a < 25% chance of being a false-positive finding (q value = 0.240). Using a multivariate model search algorithm over 11 IL18 tagging SNPs, we found that the association was best modeled by rs1834481. Further, this SNP uniquely tagged a significantly associated IL18 haplotype and there was an increased risk of epithelial ovarian cancer per rs1834481 allele (odds ratio, 1.24; 95% confidence interval, 1.06-1.45). In a replication stage, 12 independent studies from the Ovarian Cancer Association Consortium (OCAC) genotyped rs1834481 in an additional 5,877 cases and 7,791 controls. The fixed effects estimate per rs1834481 allele was null (odds ratio, 0.99; 95% confidence interval, 0.94-1.05) when data from the 12 OCAC studies were combined. The effect estimate remained unchanged with the addition of the initial North Carolina Ovarian Cancer Study data. This analysis shows the importance of consortia, like the OCAC, in either confirming or refuting the validity of putative findings in studies with smaller sample sizes. (Cancer Epidemiol Biomarkers Prev 20081-17(12):3567-72)